medwireNews: Oral semaglutide significantly reduces the risk for major adverse cardiovascular events (MACE) versus placebo in people with type 2 diabetes and atherosclerotic cardiovascular disease, chronic kidney disease, or both, phase 3 study findings indicate.
Darren McGuire (University of Texas Southwestern Medical center, Dallas, USA) and co-investigators explain that although the cardiovascular efficacy and safety of injectable semaglutide, and the cardiovascular safety of oral semaglutide have been established in people with type 2 diabetes and high cardiovascular risk, there is still a need to understand the cardiovascular efficacy of oral treatment in these patients.
To address this, they set up the international Semaglutide Cardiovascular Outcomes Trial (SOUL) recruiting patients from 444 sites in 33 countries. The study included 9650 people (71% men) aged 50 years and older with type 2 diabetes and known atherosclerotic cardiovascular disease and/or chronic kidney disease who were randomly assigned to receive once-daily oral semaglutide (3 mg starting dose increasing to a maximum of 14 mg) or placebo, alongside standard care. At baseline, the participants had a mean age of 66 years and a mean glycated hemoglobin of 8.0% (64 mmol/mol).
The researchers report in The New England Journal of Medicine that, during a mean 47.5 months of follow-up, the incidence of MACE (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) was a significant 14% lower among the 4825 participants given oral semaglutide than among the 4825 individuals given placebo, at 12.0% versus 13.8% (3.1 vs 3.7 events per 100 person–years).
Based on this difference, they calculated that 50 people would need to be treated with semaglutide to prevent one MACE.
Further analysis revealed that the difference between the two arms was driven by a significantly lower rate of nonfatal myocardial infarction with semaglutide than with placebo (4.0 vs 5.3%). There was no significant difference between the two groups in the rates of cardiovascular death (6.2 vs 6.6%) or nonfatal stroke (3.0 vs 3.3%).
There was also no significant difference between the semaglutide and placebo treatment arms in the rates of major kidney disease events (death from cardiovascular causes, kidney-related death, a persistent ≥50% reduction in estimated glomerular filtration rate [eGFR] from baseline, a persistent eGFR <15 ml/min per 1.73m2, or initiation of long-term kidney replacement therapy), at 8.4% versus 9.0% (2.1 vs 2.3 events per 100 person–years).
However, the investigators note that, among the five components of this composite outcome, death from cardiovascular causes accounted for 71.2% of the events, whereas 28.8% were kidney-related events.
McGuire et al also found that oral semaglutide use was not associated with an increased risk for serious adverse events (AEs), which occurred in 47.9% of people given the glucagon-like peptide (GLP)-1 receptor agonist and in 50.3% of those given placebo.
Nonetheless, more participants in the semaglutide arm permanently discontinued treatment due to AEs than did those in the placebo arm (15.5 vs 11.6%). Such events were mainly gastrointestinal disorders (6.4 vs 2.0%), and infections or infestations (1.3 vs 2.0%).
McGuire and co-authors conclude that the SOUL study findings “show a cardiovascular benefit of oral semaglutide and are consistent with results reported for injectable semaglutide and other GLP-1 receptor agonists with established cardiovascular efficacy.”
The data were also presented at the American College of Cardiology annual meeting (ACC.25) in Chicago, Illinois, USA.
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N Engl J Med 2025; doi:10.1056/NEJMoa2501006
ACC.25; Chicago, Illinois, USA: 29–31 March
